How the liver remembers: The science behind intermittent fasting - study

Fasting has become fashionable, not only a requirement of various religions. Not eating for a day from time to time or from sunrise to sunset for a month is an integral part of everyday life for millions of people worldwide for religious or spiritual purposes and is deeply rooted in tradition and faith.

In recent years, fasting has also become popular beyond its religious and cultural roots, embraced as a tool for improving health and promoting weight loss. Intermittent fasting, prolonged fasting, and time-restricted eating are increasingly adopted, with advocates claiming benefits such as enhanced metabolic health, weight management, and even living longer. This trend underscores the importance of understanding the physiological mechanisms underlying fasting, both in traditional contexts and as a modern lifestyle choice.

Fasting practices have raised interesting questions about how the body adapts to such recurring deprivation of food. Is it beneficial to health or harmful? 

A new, 28-page study published in the journal Nucleic Acids Research discloses how repeated fasting triggers a cellular memory mechanism in the liver, upgrading its response to future fasting events. 

Entitled “Repeated fasting events sensitize enhancers, transcription factor activity and gene expression to support augmented ketogenesis,” it was led by Dr. Ido Goldstein from the Institute of Biochemistry, Food Science, and Nutrition at the Hebrew University of Jerusalem’s Robert H. Smith Faculty of Agriculture, Food and Environment.

Goldstein and his team said that this process, driven by the transcription factor PPARa, highlights how the body adjusts to recurring nutritional challenges.

The research, based on a mouse model, uncovers a fascinating link between alternate-day fasting (ADF) and the liver’s ability to adapt through heightened gene activation and production of a fuel termed ketone bodies, offering new insights into metabolic regulation.

Episodes of fasting are an inherent aspect of physiology with most animals experiencing frequent and sometimes prolonged bouts of fasting, and they survive frequent and prolonged fasting periods due to production of glucose and ketone bodies by the liver.

The changes produced from fasting

FASTING INDUCES metabolic changes in mammals, making possible the production of glucose and ketone bodies for energy during periods when food is scarce. This process is driven by transcriptional changes in the liver – changes in the expression of genes where the information in a strand of DNA is copied into a new molecule of messenger RNA (mRNA). DNA safely and stably stores genetic material in the nuclei of cells as a reference, or template.

Goldstein told The Jerusalem Post that they had to study mice and not humans as it was not ethical because of invasive procedures that would have to be carried out, “but we know that a healthy reaction to fasting is very similar in people and mice, in which they occur faster.”

Many previous studies show that fasting can improve human health, including easing Type-2 diabetes and helping to lose weight, he said. “People who fast one day are at first very hungry, but the next day, they don’t eat twice as much, so they lose weight.”

Goldstein completed his doctorate at the Weizmann Institute of Science in 2008 and became an assistant professor at the Hebrew University. He opened his lab six years ago after becoming interested in the processes within cells and the genetics of fasting.

In 2023, he was awarded the prestigious Krill Prize for Excellence in Scientific Research for promising researchers. These prizes, which have been a prestigious annual recognition since 2005, aim to celebrate and support exceptional academic faculty members.

Spanning the fields of exact sciences, life sciences, medicine, engineering, and agriculture, the Krill Prize is bestowed upon individuals who have demonstrated remarkable research breakthroughs. The recipients are not only recognized for their past achievements but are also anticipated to play pivotal roles in leading research and academia in Israel in the future.

FOR THE new study, Goldstein and his team investigated how recurring fasting events, such as those experienced during ADF, influence this transcriptional program. Their findings revealed that mice undergoing ADF responded very differently to subsequent fasting bouts compared to mice fasting for the first time. They said their findings provide fresh insights into the metabolic benefits of fasting and its potential applications in health and dietary science.

The study identified a phenomenon termed “sensitization” in which key genes responsible for ketogenesis (the production of ketone bodies) were more strongly activated following ADF. This effect was linked to changes in the liver’s chromatin landscape, with enhancers – genomic regions that regulate gene expression – primed for stronger activation due to prior fasting experiences. These sensitized enhancers displayed increased binding of PPARα, a transcription factor critical for ketogenesis. Notably, this adaptive response was absent in hepatocyte-specific PPARα-deficient mice, highlighting PPARα’s essential role in this process.

The researchers found that the effects of ADF were conspicuous after just one week of repeated fasting, leading to augmented production of ketone bodies during subsequent fasts. During feeding periods, gene expression and ketone levels returned to baseline, showing that the sensitization effect is specific to fasting states. The health benefits of ADF, including improved lipid metabolism, seem to be linked to this enhanced ketogenic capacity and not in changes in calorie intake or body mass, which remained largely unchanged.

“Our study highlights how the liver adapts to repeated fasting through a memory-like mechanism that prepares it for future fasting bouts,” Goldstein explained. “This enhancer sensitization process underscores the liver’s remarkable ability to dynamically respond to recurring nutritional states.

The researchers concluded that their findings provide a deeper understanding of how repeated environmental signals, such as fasting, affect the behavior of cells and adaptation of the metabolism. “Beyond fasting, this research opens new ways to learn how transcriptional regulation mediates responses to other recurring environmental stimuli,” he said, “with potential applications in dietary science and metabolic health.”